Carbon-14 Birth Dating of Neurons in Addiction The dynamic turnover of neurons in the human brain is essentially unknown. Recent rodents and primates studies suggest that new neurons are not only generated throughout life, they integrate into the circuitry of the brain and actively participate in its functions throughout life. By combining biomedical approaches with recent developments in accelerator mass spectrometry (AMS), it is now possible to measure the incorporation of ambient 14C derived from above-ground nuclear bomb tests in neuronal DNA. We propose to use this novel approach to retrospectively establish the birth date of cells in adult human brain and to test for the effect of abused drugs and alcohol on cell turnover. This proposal is supported by our access to a large archived biorespository of well-characterized postmortem brain specimens from chronic substance abusers. Our hypothesis is that addiction is a condition that impairs the neural stem and progenitor cell pools in adult brain. A substantial literature describes the capacity of all addictive drugs to slow neurogenesis, but there are no studies, which have assessed the effect of abused drugs or alcohol on adult-generated neurons across the lifespan in humans. Chronic abuse of addictive drugs or alcohol may affect the stem/progenitor cell pool providing a link between dysfunctional neurogenesis and the pathobiology of addiction. We propose to map sites of neurogenesis in select regions of the adult brain to determine the effect of different classes of abused substances on cell turnover using the 14C birth dating method and AMS in parallel with immunologic detection of early fate and proliferation markers. Drug or alcohol-induced changes in hippocampal neurogenesis may be one of the underlying biological mechanisms responsible for the intractable cycle of compulsive use and failed abstinence. The proposed studies will contribute to an understanding of the neurobiology of drug and alcohol addiction, and may have important implications for the development of novel therapeutic approaches targeted to these cell populations.